[0001] This invention concerns novel amide derivatives and, more particularly, novel phenoxyacetic
acid amide derivatives containing a (2―hydroxy―3―phenoxypropyl)amino group, which
amides stimulate thermogenesis in warm-blooded animals and are of use, for example,
in the treatment of obesity and related conditions, such as obesity of mature onset
diabetes. The invention also provides pharmaceutical compositions for use in the administration
of the amide derivatives of the invention to warm-blooded animals, processes for the
manufacture of the said derivatives, and the use of the said derivatives in the treatment
of (and/or manufacture of thermogenic medicaments for use in the treatment of) obesity
and related conditions.
[0002] In European patent application, publication no.171760 there is described a series
of phenolic phenoxyacetic acid amide derivatives which are said to be ionotropic agents
of value in treating congestive heart disease. We have now discovered (and this is
a basis for the the present invention) that, surprisingly, certain novel amide derivatives
of the formula I defined below, which differ from the compounds of the art in lacking
a phenolic hydroxy group, possess significant thermogenic properties at doses which
cause relatively little cardiac stimulation, it being understood that selectivity
of thermogenic effect is an important requirement for a useful agent in the treatment
of, for example, obesity and related conditions.
[0003] According to the invention there is provided an amide derivative of the formula I
[set out hereinafter together with the other chemical formulae identified by Roman
numerals] wherein R
l is hydrogen or fluoro; R
2 is phenyl optionally bearing a halogeno, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl,
cyano or nitro substituent, (3-6C)cycloalkyl, (1-4C)alkyl in which the carbon atom
linked to the nitrogen of.NR
2R
3 bears one or two hydrogens, or R
2 is (3-4C)alkenyl, either of which latter groups may optionally bear a hydroxy, carbamoyl,
(1-4C)alkoxy, phenyl or chlorophenyl substituent; and R
3 is hydrogen, methyl or ethyl; or R
2 and R
3 together form (4-7C)polymethylene, in which one methylene unit may optionally be
replaced by oxygen or sulphur situated at least 2 carbon atoms distant from the nitrogen
atom of NR
2R
3, and in which two adjacent methylene units may optionally be replaced by 2 carbon
atoms of a benzene ring fused to said (4-7C)polymethylene, said benzene ring itself
optionally bearing a halogeno, (1-4C)alkoxy, (1-4C)alkyl, trifluoromethyl, cyano or
nitro substituent; or a pharmaceutically acceptable acid-addition salt thereof.
[0004] It will be appreciated that the compounds of formula I contain one or more asymmetric
carbon atoms and can exist as optically active enantiomers or as optically inactive
racemates. The present invention encompasses any enantiomer, racemate and/or (when
two or more asymmetric carbon atoms are present) diastereoisomer, which possesses
thermogenic properties in warm-blooded animals, it being well known in the chemical
art how to prepare individual enantiomers, for example by resolution of the racemate
or by stereospecific synthesis, and how to determine the thermogenic properties, for
example, using the standard tests described hereinafter.
[0005] The group -OCH
2CO.NR
2R
3 is generally located in the meta- or para-position relative to the oxyethylamino
side-chain, of which positions the para-position is preferred.
[0006] A preferred value for R
l is hydrogen.
[0007] A particular value for R
2 when it is (1-4C)alkyl or (3-4C)alkenyl as defined above is, for example, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, allyl or 2-methyl-2-propenyl, optionally
bearing a substituent selected from hydroxy, carbamoyl, (1-4C)alkoxy (such as methoxy
or ethoxy), phenyl and chlorophenyl (in particular, p-chlorophenyl).
[0008] A particular value for R
2 when it is phenyl is, for example, unsubstituted phenyl or phenyl bearing a substituent
selected from fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, trifluoromethyl,
cyano and nitro.
[0009] A particular value for R
2 when it is (3-6C)cycloalkyl is, for example cyclobutyl, cyclopentyl or cyclohexyl.
[0010] Specific values for optional substituents which may be present when R
2 is phenyl, or when a part of R
2 and R
3 together is a benzene moiety, as defined above, include for example:-
for halogeno, fluoro, chloro and bromo;
for (1-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy; and
for (1-4C)alkyl; methyl, ethyl, propyl, isopropyl and t-butyl.
[0011] A preferred value for R
3 is, for example, hydrogen.
[0012] A particular value for R
2 and R
3 when together they form (4-7C)polymethylene is, for example, tetramethylene or pentamethylene,
and when together they form (4-7C)polymethylene in which one methylene unit is replaced
by oxygen or sulphur is, for example, ethyleneoxyethylene or ethylenethioethylene.
[0013] Specific values for the group -NR
2R
3 include, for example, anilino, benzylamino, allylamino, cyclohexylamino, cyclopentylamino,
morpholino, piperidino, pyrrolidino, dimethylamino, diethylamino, methylamino, ethylamino,
propylamino, isopropylamino, butylamino, isobutylamino, (2-hydroxyethyl)amino, (3-hydroxypropyl)amino,
(2-methoxyethyl)amino, indolin-l-yl, 1,2,3,4-tetrahydroisoquinol-2-yl and 1,2,3,4-tetrahydroquinol-l-yl.
[0014] A preferred group of compounds of the invention comprises those compounds of formula
I wherein R
l is hydrogen; the group NR
2R
3 is (1-4C)alkylamino (in which (1-4C)alkyl is as defined hereinbefore) (and especially
methylamino or ethylamino), benzylamino, piperidino, pyrrolidino, (3-4C)alkenylamino,
morpholino or 1,2,3,4 tetrahydroisoquinol-2-yl; and the groups -OCH
2.CO.NR
2R
3 and -O.CH
2CH
2.NH- are attached in para-relationship; together with the pharmaceutically acceptable
acid-addition salts thereof.
[0015] A further preferred group of compounds comprises those compounds of formula I wherein
R
l is hydrogen; the group -NR2
R3 is methylamino, ethylamino, propylamino, isopropylamino, (2-hydroxyethyl)amino, (3-ydroxypropyl)amino,
(2-methoxyethyl)amino, (3-methoxypropylamino or 1,2,3,4-tetrahydroisoquinol-2-yl;
and the groups -OCH
2.CO.NR
2R
3 and -0.CH
2CH
2.NH- are attached in para-relationship; together with the pharmaceutically acceptable
acid-addition salts thereof.
[0016] Typical compounds of formula I are set out in the accompanying Examples. Compounds
of particular interest are those of Examples 1, 2, 5, 7, 16, 19 and 21, which are
provided, together with their pharmaceutically acceptable acidaddition salts, as a
further feature of the invention.
[0017] The compounds of formula I are basic and may be isolated and used either in the form
of the free base or of a pharmaceutically acceptable acid-addition salt thereof. Particular
examples of pharmaceutically acceptable acid-addition salts include, for example,
salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides),
sulphates and phosphates, and salts with organic acids such as succinates, citrates,
lactates, tartrates, oxalates and salts derived from acidic polymeric resins, such
as the free acid form of sulphonated polystyrene.
[0018] The novel compounds of formula I may be obtained by conventional processes of organic
chemistry well known in the art for the production of structurally analogous compounds,
for example as set out in our UK patent specification, Ser. No. 1,455,116. Such processes
are provided as a further feature of the invention and are illustrated by the following
procedures in which R
1, R
2 and R
3 have any of the meanings previously defined,-
(a) An ester of the formula II wherein R4 is (1-6C)alkoxy, phenoxy or benzyloxy, is reacted with an amine of the formula HNR2R3.
[0019] A particularly suitable value for R
4 is, for example, methoxy or ethoxy.
[0020] The process is generally performed in a suitable inert solvent or diluent, for example,
a (1-4C)alkanol such as methanol or ethanol, and at a temperature in the range, for
example, 0
0 to 60
0, optionally in a pressure vessel when a volatile amine such as methylamine is used.
The amine of the formula HNR
2R
3 is conveniently present as an excess.
[0021] The necessary starting esters may be obtained by reacting a phenol derivative of
the formula III with an alkylating agent of the formula X.CH
2.CO.R
4 wherein X is a suitable leaving group, for example, chloro, bromo or iodo, and R
4 has the meaning given above, in the presence of a base, for example as described
in the accompanying Examples. It will be appreciated that this procedure is analogous
to the process (b) below and that generally similar reaction conditions and bases
may be employed.
[0022] (b) A phenol derivative of the formula III is reacted with an alkylating agent of
the formula X.CH
2.CO.NR
2R
3 wherein X is a suitable leaving group,for example a chloro, bromo, iodo, methanesulphonyloxy
or p-toluenesulphonyloxy group.
[0023] The process is conveniently performed in the presence of an external base, for example
an inorganic base such as an alkali metal carbonate or acetate (e.g. potassium carbonate
or sodium acetate), or an alkali metal hydride (e.g. sodium hydride), and at a temperature
in the range, for example, 10 to 120°C. A suitable solvent or diluent, for example
acetone, methyl ethyl ketone, propan-2-ol, 1,2-dimethoxyethane or t-butyl methyl ether
may conveniently be used. In order to minimise side-reactions, the process may also
be carried out by pre-reacting the phenol of formula III with a suitable base to form
the corresponding salt which is then added to the alkylating agent of the formula
X.CH
2.CO.NR
2R
3.
[0024] The starting phenol derivatives of formula III may be obtained by conventional procedures
of organic chemistry. Thus, for example, they may be obtained by reaction of a phenol
of the formula IV with an epoxide of the formula V in a suitable solvent or diluent,
for example, an alcohol such as ethanol or propan-2-ol, at a temperature in the range,
for example, 10
0 to 110°C and conveniently at or near the boiling point of the reaction mixture. The
epoxides of formula V are known per se but can be made by reaction of phenol or o-fluorophenol
with ' epichlorohydrin or epibromohydrin in the presence of a suitable base such as
an alkali metal hydroxide, piperidine, morpholine or N-methylmorpholine, in a suitable
solvent or diluent such as methanol, ethanol or propan-2-ol, conveniently at or near
the boiling point of the reaction mixture.
[0025] In general, it is preferred to react the epoxide of formula V with a protected phenol
derivative of formula VI wherein Q is a suitable protecting group, such as benzyl.
In this case, following the reaction of compounds V and VI, the protecting group is
removed, for example in the case of benzyl by hydrogenolysis, for example using hydrogenation
at a pressure in the range, for example, 3 to 30 bar in the presence of a palladium-on-carbon
catalyst in an inert diluent or solvent for example, a (1-4C)alkanol (such as methanol,
ethanol or
t-butyl alcohol) or a (1-4C)alkanoic acid (such as acetic acid) and at a temperature
of, for example, 20-800C.
[0026] It is to be understood that the epoxides of formulae V may be used in their racemic
or enantiomeric forms.
[0027] (c) An amine derivative of the formula VII is reacted with an epoxide of formula
V.
[0028] It will be appreciated that this reaction is a modification of the procedure described
above for the production of the starting materials of formula III and that, therefore,
generally similar reaction conditions may be employed.
[0029] The starting amine derivatives of formula VII may be made from the corresponding
phenols of formula IV by reaction with a compound of the formula X.CH2.CONR2R3 as
defined above using analogous reaction conditions to those described above in process
(b).
[0030] (d) A protected derivative of the formula VIII wherein Q is a suitable protecting
group is deprotected.
[0031] A suitable protecting group is, for example, a hydrogenolysable group such as benzyl,
4-methoxybenzyl or 3,4-dimethoxybenzyl, which may be removed, for example by hydrogenation
using conditions similar to those defined above in the production of the starting
materials for process (b). Hydrogen pressure of, for example, 3 to 30 bar may be used
at a temperature in the general range, for example, 20° to 80
oC.
[0032] The protected derivatives of formula VIII may be obtained by using process (b) or
(c) with appropriate starting materials in which the amino group is protected with
a suitable protecting group. When Q is benzyl, the corresponding benzylated starting
materials analogous to those of formula VII may conveniently be obtained, for example,
by reductive alkylation of the compounds of formula VII with benzaldehyde in the presence
of sodium borohydride in a solvent or diluent such as methanol at 0
0 to 25
0C.
[0033] Whereafter, when a pharmaceutically acceptable acid-addition salt is required, the
compound of formula I in free base form is reacted with the appropriate acid using
a conventional procedure. For example, when a hydrogen halide salt is required, it
may conveniently be obtained by hydrogenation of the free base together with the stoichiometric
amount of the corresponding benzyl halide.
[0034] Whereafter, when an enantiomer is required, the corresponding racemate may be resolved,
for example by reaction with a suitable optically active acid using a conventional
procedure. Alternatively, one of the above processes may be carried out using an optically
active starting material.
[0035] As stated above, the compounds of formula I possess thermogenic properties and are
of use in the treatment of obesity and/or related diseases of metabolic dysfunction,
such as diabetes mellitus especially of adult onset. In addition, in some cases, the
compounds of formula I may be of value in modification of carcass composition, for
example, by increased catabolism of fat in meat producing animals, such as cattle,
pigs, sheep, goats and/or rabbits.
[0036] The thermogenic effects of compounds of formula I may be demonstrated using one or
more of the following standard tests:-(a) Rats are cold adapted by being placed in
a cold environment (4
0C) for 10 days in order to increase their capacity for thermogenesis. They are then
transferred to a thermoneutral environment (29
0C). Three hours later the core temperature is measured to determine a base-line reading
and the test compound is administered subcutaneously or orally as a solution or suspension
in 0.45% w/v aqueous sodium chloride, 0.25% w/v Polysorbate 80. After one hour, the
core temperature is again measured. In this test, a compound which causes a statistically
significant increase in the core temperature of about 0.3oC (or more) at a sub-cutaneous
dose of 15 mg/kg (or less) is considered to be significantly active. The test acts
as a model for the depressed thermogenesis which occurs during dieting.
[0037] (b) Rats are cold adapted at 40C for 4 days to increase their capacity for thermogenesis.
They are then transferred to a warm environment of 230C for 2 days. On the following
day, a test compound is administered sub-cutaneously or orally as described in (a).
Animals are sacrificed one hour later and the interscapular, brown adipose tissue
(BAT) pad is removed. BAT mitochondria are prepared by differential centrifugation
and GDP binding is determined (Holloway et al., Internal jovial Journal of Obesity,
1984, 8, 295) as a measure of thermogenic activation. Each test includes a control
which is dosed with the solution/suspension vehicle only and a positive control which
is dosed with isoprenaline (as its sulphate) at 1 mg/kg. Test compounds are routinely
dosed at 0.1, 0.3, 1.0, 3.0, and 10 mg/kg and results expressed in terms of the effect
on GDP binding produced by isoprenaline. From these results, a dose (ED
50) necessary to produce 50% of the isoprenaline effect is calculated by linear regression
analysis. Compounds are considered active in this test if they cause a significant
elevation in GDP binding as compared to controls. This test serves to indicate that
the thermogenic effects observed in test (a) are mediated through an increase in effect
on BAT rather than by some non-specific or toxic mechanism.
[0038] (c) Rats are adapted to a thermoneutral environment (29°C) for 2 weeks in order to
decrease their capacity for BAT mediated non-shivering thermogenesis. During the final
3 days the animals are trained to use an apparatus for measuring heart rate non-invasively
via foot-pad electrodes connected to an ECG integrator giving a continuous read-out
of heart rate. A test compound is administered sub-cutaneously at the ED
50 determined in test (b), and heart rate is determined 15-30 minutes after dosing.
The procedure is then repeated in subsequent tests using increasing multiples of the
ED
50 determined in test (b) until the heart rate (HR) reaches or exceeds 500 beats per
minute, allowing the dose necessary to produce a heart rate of 500 beats per minute
(D
500 dose) to be calculated.
[0039] The ratio of D
500 to ED
50 in test (b) can be defined as the selectivity index (SI) and provides a measure of
the selectivity of the compound for BAT as opposed to the cardiovascular system. Compounds
are considered to have significant selectivity which have an SI of >1. Non-selective
compounds have an SI of <1 (for example isoprenaline = 0.06).
[0040] (d) Rats are cold adapted at 4
0C for four days to increase their capacity for thermogenesis. They are then transferred
to a warm environment at 23
0C for two days. On the following day, the basal metabolic rate of the animals is determined
using a close-circuit oxygen consumption apparatus of the type described by Arundel
et al., 1984, J. Appl. Physiol. Respirat. Environ. Exercise Physiol., 1984, 57 (5)
1591-1593. The rats are then dosed (orally or sub-cutaneously) with test compound
at about (10 mg/kg) as a solution or suspension in 0.45% w/v aqueous sodium chloride,
0.25% w/v Polysorbate 80. Metabolic rate is then determined for at least one hour
after dosing. Compounds are considered active in this test if they cause a significant
increase in metabolic rate as compared to control animals (Student's t test: p <0.5)
dosed only the solution or suspension vehicle.
[0041] In the above tests, the compounds of formula I in general produce effects of the
following order without producing overt toxicity:-
test (a): increase in core temperature of about 0.5°C (or more) following a sub-cutaneous
dosage of <15 mg/kg;
test (b): sub-cutaneous ED50 for GDP binding in BAT mitochondria of 0.01-10 mg/kg; and
test (c): show an SI of >50.
By way of illustration, the compound described in the accompanying Example 1, produced
the following effects in the above test:-
(a) 2.250C at a sub-cutaneous dose of 10 mg/kg;
(b) sub-cutaneous ED509 0.133 mg/kg; oral ED50 1.18 mg/kg;
(c) D500: >13.3 mg/kg (sub-cut.); SI >100 (sub-cut.); SI >50 (oral).
[0042] By contrast, the known, structurally related compound N-methyl-2-p-(2-[(2-hydxoxy-3-[p-hydroxyphenoxy]-propyl)amino]ethoxy)phenoxyacetamide,
described in Example 2 of European patent application, publication no. 171760, produced
a temperature rise of 1.24
0C in test (a) and no significant activity in test (b), but produced a marked increase
in heart rate.
[0043] When used to produce thermogenic effects in warm-blooded animals including man, a
compound of formula I, or a pharmaceutically acceptable salt thereof as appropriate,
will be administered so that a dose in the general range 0.002-20 mg/kg, and preferably
in the range 0.02-10 mg/kg, is administered daily, given in a single dose or divided
doses as necessary. However, it will be appreciated by those skilled in the art that
dosage will necessarily be varied as appropriate, depending on the severity of the
condition under treatment and on the age and sex of the patient and according to known
medical principles.
[0044] The compounds of formula I will generally be used for medical (or veterinary) purposes
in the form of compositions comprising a compound of formula I, or a pharmaceutically
(or veterinarily) acceptable salt thereof as appropriate, as the active ingredient
together with a pharmaceutically (or veterinarily) acceptable diluent or carrier.
Such compositions are included in the invention and will typically be adapted for
oral administration (including tablets, capsules, pills, powders, solutions, suspensions
and the like) or parenteral administration (including sterile solutions, suspensions
and emulsions).
[0045] Compositions adapted for oral administration are generally preferred.
[0046] The compositions may be obtained using standard excipients and procedures well known
in the art. A unit dose form such as a tablet or capsule will usually contain, for
example 0.1-250 mg of active ingredient. The compositions may also contain other active
ingredients known for use in the treatment of obesity and related conditions, for
example appetite suppressants, vitamins and hypoglycaemic agents.
[0047] The invention will now be illustrated by the following Examples in which, unless
otherwise stated:-
a) all operations were carried out at room temperature that is at a temperature in
the range 18-260C;
b) evaporations were performed under reduced pressure on a rotary evaporator;
c) chromatography was carried out on Merck Kieselgel (Art 7734) obtainable from E
Merck, Darmstadt, Federal Republic of Germany;
d) yields are for illustration only and are not to be interpreted as the maximum attainable
by diligent process development;
e) nuclear magnetic resonance (NMR) spectra were determined at 200 MHz in d6-DMSO as solvent using tetramethylsilane (TMS) an internal standard and are expressed
in delta values (parts per million) for protons relative to TMS, using conventional
abbreviations to describe signal types; and
f) all crystalline end-products had satisfactory microanalyses and NMR spectra.
Example 1
[0048] A mixture of methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetate
(0.38 g) in methanol (20 ml) and a 33X w/v solution of methylamine in ethanol (10
ml) was allowed to stand at ambient temperature for 3 hours. The solvent was evaporated
and the residue was crystallised from ethyl acetate to give N-methyl-2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetamide
(0.24 g), mp 115°C; microanalysis: found C,63.9; H,7.0; N,7.3%; required for C
20H
26N
2O
5: C,64.2; H,7.0; N,7.5%; NMR: 1.84 (br s, 1H, NH); 2.68 (m, 5H, CH(OH).CH
2NH + NHCH
3); 2.86 (t,2H, NHCH
2CH
2O); 3.90 (m, 5H, OCH
2CH(OH) + OCH
2CH
2): 4.38 (s, 2H, OCH
2.CO); 4.80 (br s, 1H, OH); 6.80-7.00 (m, 7 aromatic H); 7.25 (m, 2 aromatic H); 7.80
(br s, 1H, CO.NH).
[0049] The starting material was obtained as follows:-
A mixture of N-benzyl-N-(2-hydroxyphenoxy- ethyl)-2-hydroxy-3-phenoxypropylamine (4.0
g), methyl bromoacetate (1.56 g), anhydrous potassium carbonate (1.7 g) and potassium
iodide (0.05 g) was stirred under reflux in dry acetone (50 ml) for 24 hours. The
reaction mixture was cooled, solid removed by filtration and solvent evaporated. The
residue of methyl 2-p-(2-[N-benzyl-(2-hydroxy-3-phenoxypropyl)-amino]ethoxy)phenoxyacetate
was dissolved in methanol (90 ml) and acetic acid (30 ml). The solution obtained was
hydrogenated in the presence of 10% w/w palladium-on-carbon (0.4 g) at about 20 bar
and 60°C for 48 hours. The mixture was cooled, solid removed by filtration and solvent
evaporated. The residual oil was dissolved in methanol and treated with a solution
of ether saturated with hydrogen chloride. The precipitated solid was crystallised
twice from methanol to give methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetate
hydrochloride, 0.22 g, mp 170°C; microanalysis: found C, 58.2; H, 6.3; N, 3.6; Cl,
8.8X; required for C20H26NClO6, C, 58.3; H, 6.31 N,3.4; Cl, 8.6%; NMR: 3.08 (dd, 1H, CHCH2NH), 3.26 (dd, lH, CHCH2NH), 3.36 (t, 2H, NHCH3CH2), 3.7 (s,3H, CO2CH3), 4.0(d,2H, OCH2CH), 4.25(m, 3H, OCH2.CHOH-), 4.74 (s, 2H, OCH2CO), 6.8-7.05 (m, 7 aromatic H), 7.31 (m,2 aromatic H). The hydrochloride (1.9 g)
was partitioned between 5% w/v sodium hydrogen carbonate solution (50 ml) and dichloromethane
(50 ml). The organic layer was dried (Mg S04) and the solvent evaporated. The residual solid was crystallised from methanol to
give methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]-ethoxy)phenoxyacetate (1.67
g). mp 116-118°C.
[0050] The starting propylamine derivative was obtained as follows:-
(a) A stirred mixture of 2-(p-hydroxyphenoxy)ethylamine (4.0 g) and benzaldehyde (5.0
g) in methanol (50 ml) was cooled with ice and sodium borohydride (2.0 g) was added
in portions over one hour. After stirring for a further 18 hours the solvent was evaporated.
The residue was partitioned between 2M hydrochloric acid (200 ml) and ethyl acetate
(100 ml). The acid layer was separated, made alkaline with potassium carbonate and
then extracted with ethyl acetate. The extracts were dried (MgS04) and evaporated. The residual oil was dissolved in ethyl acetate and dry hydrogen
chloride was passed through the solution until no further solid precipitated. The
precipitate was collected and recrystallised from methanol and ethyl acetate to give
N-benzyl-2-(p-hydroxyphenoxy)ethylamine hydrochloride *(2.3 g), mp 182-184°C.
(b) N-Benzyl-2-(p-hydroxyphenoxy)ethylamine hydrochloride (3.5 g) was shaken with
1M sodium hydroxide solution (20 ml) and dichloromethane (20 ml). The organic layer
was separated and washed with water (10 ml), dried (MgS04) and the solvent evaporated to give N-benzyl-2-(p-hydroxyphenoxy)ethylamine as an
oil.
(c) A mixture of N-benzyl-2-(p-hydroxyphenoxy)-ethylamine (2.5 g) and 1,2-epoxy-3-phenoxypropane
(1.54 g) in propan-2-ol (50 ml) was heated under reflux for 72 hours. The solvent
was removed by evaporation to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-2-hydroxy-3-phenoxypropylamine
as an oil which was essentially pure as indicated by thin layer chromatography (TLC)
[using silica plates and 5% methanol in dichloromethane as eluant] and was used without
purification.
[0051] * The starting N-benzyl-2-(p-hydroxyphenyl)ethylamine hydrochloride may also be obtained
as followss-
A mixture of r(2-bromoethoxy)phenol (2.2 g), benzylamine (1.07 g) and triethylamine
(1.01 g) in ethanol (30 ml) was heated under reflux for 18 hours. The solvent was
evaporated and the residue was partitioned between 2M hydrochloric acid (100 ml) and
ethyl acetate (50 ml). The acid layer was separated, made alkaline with potassium
carbonate and then extracted with ethyl acetate. The extracts were dried (MgS04) and the solvent was evaporated. The residual oil was dissolved in ethyl acetate.
Dry hydrogen chloride was then passed through the solution until no further solid
precipitated. The solid was collected by filtration and recrystallised from a mixture
of methanol and ethyl acetate to give N-benzyl-2-(p-hydroxyphenoxy)ethylamine hydrochloride,
0.9g, mp 182-1840C.
Example 2
[0052] The procedure described in Example 1 may be repeated using the (-)-enantiomeric form
of methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetate (Z) (0.66
g) to obtain the corresponding optically active form of N-methyl-2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetamide
(0.50 g), m.p. 114-116°C, 25[a]D- -8.1
0(C-0.97, ethanol).
[0053] The starting material (Z) is available as follows.-
[0054] A mixture of methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetate,
(0.92 g), (-)-dip-toluoyltartaric acid monohydrate (0.991 g) in methanol (15 ml) was
evaporated by boiling to give a final volume of 5 ml. Methyl acetate (10 ml) was added
and the mixture was again concentrated to 5 ml volume. This treatment was repeated
once more. The mixture was left at ambient temperature for 18 hours. The solid which
had formed was collected and crystallised from methanol and methyl acetate to give
(-)-methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetate (-)-di-p-toluoyltartrate,
(0.337 g); mp 146-148
0C;
25[a]
D - -80.3
0 (C=0.97; methanol).
[0055] (-)
-Methyl 2-p-(2-[(2-hydroxy-3-phenoxypropyl)-amino]ethoxy)phenoxyacetate (-)-di-p-toluoyltartrate
(0.33 g) was partitioned between 5% w/v sodium hydrogen carbonate solution (10 ml)
and dichloromethane (10 ml). The organic layer was separated, dried (MgS0
4) and the solvent was evaporated. The residual solid,(0.148 g), mp 114-116°C, 23
[α]D = -7.8
0 (C=0.97; dichloromethane), was dissolved in methyl acetate. Dry hydrogen chloride
gas was passed through the solution until no further solid precipitated. The precipitate
was collected and crystallised from methanol and methyl acetate to give (-)-methyl
2-p-(2-[(2 hydroxy-3-phenoxypropyl)amino]-ethoxy)phenoxyacetate hydrochloride, (0.092
g), mp 156-157°C, 23
[α]D = -12.1
0 (C=1.0; methanol).
Examples 3-16
[0056] Using a similar procedure to that described in Example 1 (but using the appropriate
amine of the formula H.NR
2R
3 and carrying out the reaction essentially to completion as judged by thin layer chromatographic
[TLC] analysis on silica), there were obtained the following compounds of the formula
IX in yields of 60 to 90%, isolated either as the free base or the hydrochloride or
oxalate salt by reaction of the free base with ethereal hydrogen chloride or oxalic
acid and recrystallisation from the indicated solvents:-

[0057] The starting ester for Example 4 was obtained as follows a-
(i) A mixture of resorcinol (88 g), 1,2-dibromoethane (180 g) and potassium hydroxide
(44.8 g) was stirred under reflux in methanol (600 ml) for 24 hours. The reaction
mixture was cooled. The residual solid was removed by filtration and the filtrate
was evaporated to give 3-(2-bromoethoxy)phenol as an oil which was essentially pure
as indicated by TLC [using silica plates and 10% v/v methanol in dichloromethane as
eluant] and was used without purification.
(ii) A mixture of 3-(2-bromoethoxy)phenol (40 g) and benzylamine (39.2 g) was stirred
under reflux in ethanol (800 ml) for 18 hours. The reaction mixture was cooled and
the solvent evaporated. The residual oil was dissolved in ethyl acetate (200 ml).
The solution was washed with 2M hydrochloric acid (100 ml). The aqueous layer was
basified with solid potassium carbonate and extracted with ether (2 x 100 ml). The
extracts were washed successively with water (50 ml) and brine (50 ml), and were then
dried (MgS04). The dry ethereal solution was treated with a solution of ether saturated with hydrogen
chloride. The precipitated solid was crystallised twice from a mixture of methanol/ethyl
acetate to give N-benzyl-2-(m-hydroxyphenoxy)ethylamine hydrochloride (19.2 g), mp
148-149°C; NMR: 3.2 (t,2H, CH2NH), 4.22 (s + t, 4H, CH2O, NCH2Ph), 6.4 (m,3 aromatic H), 7.1 (t,l aromatic H), 7.3-7.8 (m,5 aromatic H).
(iii) A mixture of N-benzyl-2-(m-hydroxyphenoxy)ethylamine hydrochloride (2.79 g),
1,2-epoxy-3-phenoxypropane (1.5 g) and anhydrous potassium carbonate (2.0 g) was heated
under reflux in propan-2-ol for 18 hours. The reaction mixture was cooled and the
solvent was evaporated to give N-benzyl-N-(2-m-hydroxyphenoxyethyl)-2-hydroxy-3-phenoxypropylamine
as an oil, which was essentially pure as indicated by TLC [using silica plates and
5% methanol in dichloromethane as eluant] and was used without purification.
(iv) N-Benzyl-N-(2-m-hydroxyphenoxyethyl)-2-hydroxy-3-phenoxypropylamine (1.6g) was
reacted with methyl bromoacetate (0.5g), anhydrous potassium carbonate (0.6 g) and
potassium iodide (0.05 g) in acetone (80 ml), using a similar procedure to that described
for the starting ester in Ex.l and with intermediate isolation of methyl 2-m-(2-[N-benzyl-(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetate
(1.1 g). There was obtained methyl 2-m-(2-[(2-hydroxy-3-phenoxypropyl)amino]-ethoxy)phenoxyacetate
hydrochloride (0.35 g), mp 164-167°C; microanalysis, founds C, 58.01 H,6.5; N,3.3; Cl, 8.7%; required for C20H26NClO6; C, 58.3; H,6.4; N,3.4; Cl, 8.6%; NMR: 3.1 (dd,lH, CHCH2NH), 3.25 (dd,lH, CHCH2NH), 3.4 (t,2H, NHCH2CH2), 3.7 (s,3H, C02CH3), 3.9-4.1 (m,2H, OCH2CH), 4.2-4.4 (m,3H, OCH2.CHOH-), 4.78 (s,2H, OCH2CO) 5.98 (d,lH, CHOH), 6.5-6.7 (m, 3 aromatic H), 6.9-7.0 (m,3 aromatic H), 7.1-7.4
(m,3 aromatic H), 9.1 (s,2H, NH2+).
Examples 17-18
[0058] Using a similar procedure to that described in Examples 3-16, but starting from methyl
2-p-(2-[(3-o-fluorophenoxy-2-hydroxypropyl)amino]ethoxy)phenoxyacetate, there were
obtained in yields of approximately 80-90%:-
(Example 17) N-methyl-2-p-(2-[(3-o-fluorophenoxy-2-hydroxypropyl)amino]ethoxy)phenoxyacetamide
as its hydrochloride salt, mp 168-1690C (recrystallised from methanol/ethyl acetate); and
(Example 18): N-piperidino-2-p-(2-[(3-o-fluorophenoxy-2-hydroxypropyl)amino]ethoxy)phenoxyacetamide
as its hydrochloride salt, mp 144-1460C (recrystallised from ether/methanol).
[0059] The required starting methyl ester was obtained as follows.
(i) A mixture of N-benzyl-2-(p-hydrpxyphenoxy)ethylamine hydrochloride (see Example
1) (5.6 g), 1,2-epoxy-3-o-fluorophenoxypropane (3.6 g) and anhydrous potassium carbonate
(2.7g) was heated under reflux in propan-2-ol (100 ml) for 24 hours. The reaction
mixture was cooled, the solid removed by filtration and the solvent evaporated from
the filtrate. The residual oil was purified by chromatography on silica eluting with
1% v/v methanol in dichloromethane to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-3-o-fluorophenoxy-2-hydroxypropylamine
as a colourless oil; NMR: 2.27-3.15 (m, 4H, CH2NCH2), 3.8 (dd,2H, NCH2Ph), 3.9-4.2 (m,5H, OCH2.CHOH, o-F-Ph.OCH2), 6.7 (s, 4 aromatic H), 6.8-7.1 (m, 4 aromatic H), 7.3 (m,5H, CH2Ph).
(ii) A mixture of N-benzyl-N-(2-p-hydroxyphenoxyethyl)-3-o-fluorophenoxy-2-hydroxypropylamine
(5.4 g), methyl bromoacetate (2.0 g), anhydrous potassium carbonate (1.79) and potassium
iodide (0.05 g).was stirred under reflux in dry acetone (80 ml) for 24 hours. The
reaction mixture was cooled, solid removed by filtration and the solvent evaporated.
The residue was dissolved in dichloromethane (40 ml) and washed successively with
10% w/v sodium bicarbonate solution (20 ml) and water (20 ml), then dried (MgS04) and the solvent removed by evaporation. The oil (6.18 g) obtained was purified by
chromatography on silica, eluting with 1% v/v methanol in dichloromethane to give
methyl 2-p-(2-[N-benzyl-(3-o-fluorophenoxy-2-hydroxypropyl)amino]ethoxy)phenoxyacetate
as a colourless oil. This was dissolved in methanol (100 ml) and stirred with decolourising
charcoal (1 g) for 1 hour. The charcoal was removed by filtration and the filtrate
was hydrogenated in the presence of benzyl chloride :0.71 g) and 10% w/w palladium-on-carbon
for 2 hours at atmospheric pressure. The catalyst was removed by filtration and the
solvent was evaporated from the filtrate. The residual solid was crystallised twice
from a mixture of methanol and anhydrous ether to give methyl 2-p-(2-[(3-o-fluorophenoxy-2-hydroxypropyl)amino]ethoxy)phenoxyacetate
hydrochloride (0.55 g), mp 120-122°C; microanalysis, found, C,55,7; H,5.9; N,3.2;
C1,8.3%; required for C20H25NClFO6: C,55.9; H,5.9; N,3.3, Cl, 8.2%; NMR: 3.1 (dd, 1H, CHCH2NH), 3.27 (m under HOD peak, 1H, CH.CH2NH), 3.41 (t,2H, NHCH2CH2), 3.68 (s,3H), C02CH3), 4.05 (d, 2H, OCH2CH), 4.25 (d+m, 3H, OCH2, CHOH), 4.71, (s, 2H, OCH2CO), 5.93 (d,lH, CHOH), 6.8-7.0 (m, 5 aromatic H), 7.1-7.3 (m, 3 aromatic H), 9.12
(broad s, 2H, NH2+).
Example 19
[0060] Using a similar procedure to that described in Example 2, the (-)-enantiomeric phenoxyacetate
(Z) (0.6 g) was converted to N-(2-hydroxyethyl)-2-p-(2-[(2-hydroxy-3-phenoxypropyl)aminol
ethoxy)phenoxyacetamide (0.32 g), mp 111-113°C, 25
[α]D= -7.1
0 (C=0.99; ethanol), using ethanolamine in place of methylamine.
Examples 20-27
[0061] Using a similar procedure to that described in Example 1 (but using the appropriate
amine of the formula H.NR
2R
3 and carrying out the reaction essentially to completion as judged by TCL analysis
on silica), the following compounds of the formula IX (substituent -OCH
2CO.NR
2R
3 located in position 4 of ring X) were obtained in yields of 55 to 85X, isolated as
the free bases and after recrystallisation from the indicated solvents:-

Example 28
[0062] Sodium hydride (0.132 g of a 60% w/w suspension in mineral oil) was added to p-(2-[2-hydroxy-3-phenoxyp-ropylamino]-ethoxy)phenol
(1.0 g) dissolved in dry dimethylformamide (DMF) (50 ml). The resulting suspension
was stirred for approximately 30 minutes until a clear solution was obtained. A solution
of N-phenyl-2-chloroacetamide (0.559 g) in dry DMF (20 ml) was added and the mixture
was stirred for 18 hours. It was then poured into water (150 ml). The mixture obtained
was extracted with dichloromethane (2 x 100 ml). The extracts were washed with water
(6 x 100 ml), then dried (MgS0
4) an the solvent evaporated. The residue was crystallised from ethyl acetate to give
N-phenyl-2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)-phenoxyacetamide (0.365
g), mp 119-121°C; microanalysis; found
C, 68.7, H, 6.5, N, 6.3, required for C
25H
28N
2O
5; C, 68,8; H 6.4; N, 6.4%; and having a satisfactory NMR spectrum.
[0063] The starting phenol was obtained as follows:-
(i) A mixture of p-(2-aminoethoxy)phenol hydrochloride (1.89 g) triethylamine (1.01
g) and 1,2-epoxy-3-phenoxypropane (1.5 g) was heated under reflux for 24 hours. The
reaction mixture was cooled and the solvent was evaporated. The residue was partitioned
between dichloromethane (100 ml) and 10% w/v potassium carbonate solution. The organic
layer was separated, dried (MgS04), and the solvent was evaporated. The residual oil was dissolved in ethyl acetate
and dry hydrogen chloride was passed through the solution until no further solid precipitated.
The precipitate was collected and recrystallised from methanol and ethyl acetate to
give p-(2-[2-ydroxy-3-phenoxypropylamino)-ethoxy)phenol hydrochloride (0.53 g), mp,
171-72°C; microanalysis: found C,60.3; H,6.71 N,4.0; Cl, 10.6X; required for C17H22NClO4: C,60.1; H,6.5; N,4.1; C1,10.5%.
(ii) The hydrochloride salt (1.5 g), obtained by procedure (i), was partitioned between
5X w/v aqueous sodium hydrogen carbonate solution (15 ml) and dichloromethane (15
ml). The organic phase was separated, dried (MgS04) and the solvent was removed by evaporation to give p-(2-[2-hydroxy-3-phenoxypropyl-
amino]ethoxy)phenol as a stiff syrup (1.1 g), which was used without further purification.
[0064] N-Phenyl-2-chloroacetamide was obtained as follows:-
A mixture of aniline (9.3 g) and triethylamine (10.1 g) in dichloromethane (40 ml)
was added dropwise during 1 hour to an ice-cooled solution of chloroacetyl chloride
(11.3 g) in dichloromethane (40 ml). The mixture was further stirred for 18 hours.
The organic phase was separated by filtration, washed with water (3 x 50 ml), dried
(MgS04) and the solvent removed by evaporation to give N-phenyl-2-chloroacetamide (6.1 g)
as a white solid, mp 128-129°C, which was used without further purification.
Example 29
[0065] Using an analogous procedure to that described in Example 28, but using N-propyl-2-chloroacetamide
(0.447 g) in place of N-phenyl-2-chloroacetamide, there was obtained N-propyl-2-p-(2-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)-phenoxyacetamide
(0.47 g), mp 105-107
0C (recrystallised from ethyl acetate), essentially identical in all respects to the
material obtained in Example 16.
[0066] The starting N-propyl-2-chloroacetamide was obtained in an analogous manner to that
for N-phenyl-2-chloroacetamide i.e. by reacting propylamine with chloroacetyl chloride.
It was obtained as an oil which was used without special purification.
Example 30
[0067] As stated previously, suitable pharmaceutical compositions of compounds of formula
I defined hereinbefore may be obtained by standard formulation techniques.
1. An amide derivative of the formula I [set out below] wherein Rl is hydrogen or fluoro; R2 is phenyl optionally bearing a halogeno, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl,
cyano or nitro substituent, (3-6C)cycloalkyl, (1-4C)alkyl in which the carbon atom
linked to the nitrogen of NR2R3 bears one or two hydrogens, or R2 is (3-4C)alkenyl, either of which latter groups may optionally bear a hydroxy, carbamoyl,
(1-4C)alkoxy, phenyl or chlorophenyl substituent; and R3 is hydrogen, methyl or ethyl; or R2 and R3 together form (4-7C)polymethylene, in which one methylene unit may optionally be
replaced by oxygen or sulphur situated at least 2 carbon atoms distant from the nitrogen
atom of NR2R3, and in which two adjacent methylene units may optionally be replaced by 2 carbon
atoms of a benzene ring fused to said (4-7C)polymethylene, said benzene ring itself
optionally bearing a halogeno, (1-4C)alkoxy, (1-4C)alkyl, trifluoromethyl, cyano or
nitro substituent; or a pharmaceutically acceptable acid-addition salt thereof.
2. A compound as claimed in claim 1 wherein R2 is phenyl optionally bearing a substituent selected from fluoro, chloro, bromo, methoxy,
ethoxy, methyl, ethyl, trifluoromethyl, cyano and nitro substituents; cyclobutyl,
cyclopentyl or cyclohexyl; or is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
allyl or 2-methyl-2-propenyl, optionally bearing a substituent selected from hydroxy,
carbamoyl, methoxy, ethoxy, phenyl and p-chlorophenyl; or R2 and R3 together form ethyleneoxyethyleue or ethylenethioethylene, or together form tetramethylene
or pentamethylene, two adjacent methylene units of which may optionally be replaced
by 2 carbon atoms of a benzene ring fused to said tetramethylene or pentamethylene,
said benzene ring itself optionally bearing a fluoro, chloro, bromo, methoxy, ethoxy,
methyl, ethyl, trifluoromethyl, cyano or nitro substituent.
3. A compound as claimed in claim 1 or 2 wherein the group NR2R3 is selected from anilino, benzylamino, allylamino, cyclohexylamino, cyclopentylamino,
morpholino, piperidino, pyrrolidino, dimethylamino, diethylamino, methylamino, ethylamino,
propylamino, isopropylamino, butylamino, isobutylamino, (2-hydroxyethyl)amino, (3-hydroxypropyl)amino,
(2-methoxyethyl)amino, indolin-l-yl, 1,2,3,4-tetrahydroisoquinol-2-yl and 1,2,3,4-tetrahydroquinol-1-yl.
4. A compound as claimed in any one of claims 1-3 wherein the the groups -OCH2.CO.NR2R3 and -O.CH2CH2.NH- are attached in para-relationship.
5. A compound as claimed in claim 1 wherein R2 is (1-4C)alkyl optionally bearing a hydroxy or (1-4C)alkoxy substituent and in which
the carbon atom linked to the nitrogen of NR2R3 bears one or two hydrogens; R3 is hydrogen, methyl or ethyl; or R2 and R3 together form (4-6C)polymethylene in which one methylene unit may optionally be replaced
by oxygen or sulphur situated at least 2 carbon atoms distant from the nitrogen atom
of NR2R3.
6. A compound of the formula I [set out below] wherein Rl is hydrogeni the group NR2R3 is benzylamino, piperidino, pyrrolidino, (3-4C)alkenylamino, morpholino, 1,2,3,4-tetrahydroisoquinol-2-yl
or (1-4C)alkylamino in which the carbon atom linked to the nitrogen bears one or two
hydrogens; and the groups -0CH2.CO.NR2R3 and -O.CH2CH2.NH- are attached in para- relationships or a pharmaceutically acceptable acid-addition
salt thereof.
7. A compound of the formula I [set out below] wherein Rl is hydrogen; the group -NR2R3 is methylamino, ethylamino, propylamino, isopropylamino, (2-hydroxyethyl)amino, (3-hydroxypropyl)amino,
(2-methoxyethyl)amino, (3-methoxypropyl)amino or 1,2,3,4-tetrahydroisoquinol-2-yl;
and the groups -OCH2.CO.NR2R3 and -O.CH2CH2.NH- are attached in para-relationship; or a pharmaceutically acceptable acid-addition
salt thereof.
8. A compound selected from N-methyl-, N-propyl-, N-(2-hydroxyethyl)- and N-allyl-2-p-(2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy)phenoxyacetamide,
and from the pharmaceutically acceptable acid-addition salts thereof.
9. A salt as claimed in any one preceding claim which is with an inorganic or organic
acid affording a pharmaceutically acceptable anion.
10. A pharmaceutical composition comprising a compound of the formula I, or a pharmaceutically
acceptable acid-addition salt thereof, as defined in any one preceding claim, together
with a pharmaceutically acceptable diluent or carrier.
11. A process for the manufacture of a compound of the formula I, or a pharmaceutically
acceptable acid-addition salt thereof, as defined in any one preceding claim and wherein
R
1,
R2 and R
3 have any of the meanings defined in claims 1-7, which is characterised in that:
(a) an ester of the formula II wherein R4 is (1-6C)alkoxy, phenoxy or benzyloxy, is reacted with an amine of the formula HNR2R3;
(b) a phenol derivative of the formula III is reacted with an alkylating agent of
the formula X.CH2.CO.NR2R3 wherein X is a leaving group;
(c) an amine derivative of the formula VII is reacted with an epoxide of formula V;
or
(d) a protected derivative of the formula VIII wherein Q is a protecting group is
deprotected;
whereafter when a pharmaceutically acceptable acid-addition salt is required, the
compound of formula I in free base form is reacted with the appropriate acid using
a conventional procedure; and
when an enantiomer of a compound of formula I is required, the corresponding racemate
may be resolved or one of the above procedures (a)-(d) may be carried out using an
optically active starting material; and wherein the formulae II, III, V, VII and VIII
are set out below.
1. A process for the manufacture of an amide derivative of the formula I [set out
below] wherein R
l is hydrogen or fluoro; R
2 is phenyl optionally bearing a halogeno, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl,
cyano or nitro substituent, (3-6C)cycloalkyl, (1-4C)alkyl in which the carbon atom
linked to the nitrogen of NR
2R
3 bears one or two hydrogens, or R
2 is (3-4C)alkenyl, either of which latter groups may optionally bear a hydroxy, carbamoyl,
(1-4C)alkoxy, phenyl or chlorophenyl substituent; and R
3 is hydrogen, methyl or ethyl; or R
2 and R
3 together form (4-7C)polymethylene, in which one methylene unit may optionally be
replaced by oxygen or sulphur situated at least 2 carbon atoms distant from the nitrogen
atom of NR
2R
3, and in which two adjacent methylene units may optionally be replaced by 2 carbon
atoms of a benzene ring fused to said (4-7C)polymethylene, said benzene ring itself
optionally bearing a halogeno, (1-4C)alkoxy, (1-4C)alkyl, trifluoromethyl, cyano or
nitro substituent; or a pharmaceutically acceptable acid-addition salt thereof which
is characterised in that:
(a) an ester of the formula II wherein R4 is (1-6C)alkoxy, phenoxy or benzyloxy, is reacted with an amine of the formula HNR2R3,
(b) a phenol derivative of the formula III is reacted with an alkylating agent of
the formula X.CH2.CO.NR2R3 wherein X is a leaving group;
(c) an amine derivative of the formula VII is reacted with an epoxide of formula V;
or
(d) a protected derivative of the formula VIII wherein Q is a protecting group is
deprotected,
whereafter when a pharmaceutically acceptable acid-addition salt is required, the
compound of formula I in free base form is reacted with the appropriate acid using
a conventional procedure; and
when an enantiomer of a compound of formula I is required, the corresponding racemate
may be resolved or one of the above procedures (a)-(d) may be carried out using an
optically active starting material; and wherein R
1, R
2 and R
3 have any of the meanings defined above and the formulae II, III,. V , VII and VIII
are set out below.
2. A process according to part (a) of claim 1 characterised in that it is performed
in a suitable inert solvent or diluent and at a temperature in the range 0° to 60oC, optionally in a pressure vessel when HNR2R3 is a volatile amine.
3. A process according to part (b) of claim 1 characterised in that X is chloro, bromo,
iodo, methanesulphonyloxy or p-toluenesulphonyloxy.
4. A process according to part (b) of claim 1 or claim 3 characterised in that an
external base is present and the reaction is performed at a temperature in the range
10° to 1200C.
5. A process according to part (c) of claim 1 characterised in that it is performed
in a suitable diluent or solvent and at a temperature in the range 10° to 110°C.
6. A process according to part (d) of claim 1 characterised in that Q is a hydrogenolysable
protecting group and the deprotection is carried out by catalytic hydrogenation in
a suitable solvent or diluent and at a temperature of 20° to 800C.
7. A process according to any one of claims 1-6 for the production of a hydrohalide
salt of a compound of formula I characterised in that as an additional step the free
base form of said compound is hydrogenated in the presence of a stoichiometric amount
of a benzyl halide corresponding to the hydrohalide salt required.
8. A process according to any one preceding claim wherein in the starting materials
Rl is hydrogen, the group -NR2R3 is methylamino, ethylamino, propylamino, isopropylamino, (2-hydroxyethyl)amino, (3-hydroxypropyl)anino,
(2-methoxyethyl)amino, (3-methoxypropylamino or 1,2,3,4-tetrahydroisoquinol-2-yl;
and the groups -OCH2.CO.NR2R3 and -O.CH2CH2.NH- are attached in para-relationship.
9. A process for the manufacture of a novel pharmaceutical composition which comprises
mixing a compound of the formula I, or a pharmaceutically acceptable acid-addition
salt thereof, as defined in claim 1, with a pharmaceutically acceptable diluent or
carrier.